Quantity and Functional Exhaustion of Mucosal-Associated Invariant T Cells in Acute Myeloid Leukemia: Friends or Foes?

Abstract

Introduction

Acute Myeloid Leukemia (AML) is a hematological malignancy affecting hematopoietic progenitor cell differentiation, proliferation, and cell cycle progression, possibly involving disturbances in host immune function. Comprehensive understanding of the immune system composition and function in AML patients is crucial for developing novel immunotherapeutic strategies. Mucosa-Associated Invariant T cells (MAITs), as a subset of unconventional T cells, bridge innate and adaptive immunity and have been predominantly studied in the context of mucosa-related cancers. However, their role in AML remains largely unexplored. Investigating the association between MAITs and AML is of significant importance for understanding the immune escape mechanisms in AML, developing novel immunotherapeutic approaches, and predicting patient prognosis.

Methods

This study aimed to delineate the longitudinal immune profile of MAITs during AML pathogenesis and treatment, which may contribute to understanding immunological changes of MAITs in AML and predicting patient prognosis. In this prospective study, we collected peripheral blood or bone marrow samples from 131 AML patients, including 99 newly diagnosed cases, 18 in remission, and 14 in relapse, as well as 69 healthy controls. We performed multi-parameter flow cytometry for phenotypic and functional analysis of MAITs and explored their relationship with disease features, progression, and prognosis.

Results

We initially demonstrated that MAITs reflected immunological defects in AML patients. MAITs showed signs of depletion in both frequency and absolute count at initial diagnosis (p<0.0001) (Fig. 1A), especially in the CD8 ⁺ MAITs subset. The frequency of MAITs reflected AML cell genetics, tumor burden, disease status, and treatment responsiveness (Fig. 1B). AML patients exhibited reduced frequency of effector memory MAITs (p<0.0001) and increased frequency of terminal differentiated MAITs (p<0.0001) in peripheral blood (Fig. 1C), indicating altered reactivity of MAIT cells to antigen stimulation. MAITs displayed a state of high activation and even exhaustion, as evidenced by upregulated PD-1 expression. Impaired secretion of Th1-type cytokines and increased secretion of Th17-type cytokines (Fig. 1D), granzyme B, and perforin were observed in MAITs, while MAITs also shifted towards secreting tumor-promoting cytokines such as IL-8. Lower frequency of MAITs was correlated with inferior Overall Survival (OS) and Progression-Free Survival (PFS) (Fig. 1E). Multivariate analysis identified MAITs frequency <2.12% as an independent prognostic factor affecting OS.

Conclusion

Our study highlights the role of MAITs in immunological defects in Acute Myeloid Leukemia and reveals their functional impairment and enhanced tumor-promoting effects. The frequency of MAITs in peripheral blood reflects the genetic features, tumor burden, disease status, and treatment responsiveness of AML patients. Lower frequency of MAITs is associated with inferior OS and PFS, serving as a prognostic indicator for AML.